Perindopril (Formula IA) and its pharmaceutically acceptable salts, especially the tert. butylamine salt (Formula IB), have valuable pharmacological properties. Their main property lies in the inhibition of the enzyme that converts angiotensin I (or kininase II), a precursor for formation of angiotensin II enzyme, thereby enables on the one hand prevention of the conversion of the decapeptide angiotensin I to the octapeptide angiotensin II (vasoconstrictor) and on the other hand prevention of the degradation of bradykinin (vasodilator) to inactive peptide. These two actions contribute to the beneficial effects of perindopril or its salts in cardiovascular disorders, especially arterial hypertension and cardiac insufficiency. The use of perindopril in these therapies demands high purity of the final compound in a manufacturing operation.
Perindopril, its preparation and its therapeutic use were first described in European Patent Specification No. 0049658.
An alternative route of synthesis for perindopril has been reported in Tetrahedron Letters 23, (16), 1677-1680, (1982), wherein the tert. butyl ester of (2S, 3aS, 7aS)-octahydroindole-2-carboxylic acid was coupled with N-[(S)-1-carboxybutyl]-(S)-alanine ethyl ester (Formula III) in presence of triethyl amine, dicyclohexylcarbdiimide(DCC), and 1-hydroxy benzotriazole(HOBT) and subsequently deprotecting the tert. butyl ester protective group from the resultant intermediate. The tert. butyl amine (erbumine) salt of perindopril was reported for the first time in the above publication.
Subsequently, European patent No. 0308341 has disclosed a similar process for perindopril claimed to be an industrial process by the reaction of (2S, 3aS, 7aS)-octahydroindole-2-carboxylic acid esters of Formula II with N-[(S)-1-carboxybutyl]-(S)-alanine ethyl ester of Formula III using triethylamine, DCC and HOBT to give the compound of Formula IV followed by de-protection of ester group selectively by methods known in the art to get perindopril (Formula IA). The ester forming groups for (2S, 3aS, 7aS)-octahydroindole-2-carboxylic acid ester are selected from benzyl, and alkyl groups. Perindopril erbumine salt (Formula IB) is then obtained by combining tert. butylamine with Perindopril (Formula IA).
However, the product obtained by the above process contains many impurities thereby making the product isolation difficult even on laboratory scale, as also observed by others, and the process improvement taking care of a part of the problems has been the subject of patent applications No. U.S. 2003/0069431 and WO 0364388.
The United States patent application 2003/0069431 describes a modified process for the manufacture of Perindopril and its tert. -butyl amine salt using the same reactants. It discloses the reaction of benzyl ester of (2S, 3aS, 7aS)-octahydroindole-2-carboxylic acid with N-[(S)-1-carboxybutyl]-(S)-alanine ethyl ester in solvent ethyl acetate, in presence of reduced molar quantities of HOBT, DCC and in presence or absence of triethyl amine, whereby the impurities of Formula VII & Formula VIII in perindopril are brought down to below 0.1 and 0.2% respectively but with extra purifications.


According to the process mentioned in patent application No. WO 03/064388, the compound of Formula III is N-protected by suitable carbonic acid derivatives. The carboxylic acid group is then converted into its acid chloride, followed by its reaction with octahydroindole-2-carboxylic acid, yielding perindopril of better purity. It also avoids use of DCC. Various other process-patents such as EP1371659, EP1380591, EP1380590, EP 1362864, EP1367061 are published, and claimed to minimize the problems associated with prior art i.e. purity of Perindopril. In these reports, the route of synthesis and the intermediates are different than the processes, discussed above.

A thorough study of prior art indicates that the process route disclosed in Tetraherdon Letters 1982, 23(16), 1677-1680, is the best suited as an industrial route and comparatively more economical to produce Perindopril or its erbumine salt, provided it avoids the formation of impurities as well as eliminates need for additional purification steps. Patent application WO 01/58868 addressed this problem to some extent by reducing two impurities having Formula VII and VIII to give improved quality of the product.
The processes mentioned in patents EP 0308341 and WO 01/58868 describe the use of ethyl acetate as a solvent in the amino acid coupling step. Under the conditions of coupling, one major impurity, viz. N-acetyl (2S, 3aS, 7aS)-octahydroindole-2-carboxylic acid benzyl ester (Formula V), is formed. Formation of this impurity has been identified to be associated with the use of ethyl acetate as solvent. The reason being ethyl acetate acting as acylating agent to form the impurity of Formula V. Removal of this impurity is very difficult at this stage, as the nature of the impurity and the resultant coupled products is very similar. It is also difficult to remove the impurity in the next step i.e. debenzylation. The coupled product (Formula IV) gives Perindopril (Formula IA) whereas compound of Formula V also gets debenzylated to form N-acetyl (2S, 3aS, 7aS) octahydroindole-2-carboxylic acid (Formula VI), which again contaminates as an impurity in final perindopril. Since the heterocyclic part containing the carboxylic acid group is present in both Perindopril (Formula IA) and in this impurity (Formula VI) and due to this, during salt formation of Perindopril with tert. -butylamine, compound of Formula VI invariably remains contaminated with the final perinodpril erbumine salt (Formula IB).

Yet another report (WO 2004/099138), disclosed a debenzylation of benzylperindopril in presence of tert.butylamine to directly isolate perindopril erbumine salt after debenzylation. Although this process reduces one process operation, i.e., tert. butylamine salt formation, but the process does not take care of impurities generated in the peptide coupling stage, i.e., the benzyl perindopril formation and there is no report on the effective means for purification of the product. This again leads to repeated purification of the final perindopril erbumine salt to get a pharmaceutically acceptable purity.
Although the impurities formation can be controlled to some extent by varying solvents or by changing the coupling catalysts, but the problems of isolation & purification of the benzyl perindopril as well as resulting perindopril still remains. Since there is no effective means for a purification of benzyl perindopril, which is an oily product, it is difficult to ensure the purity of benzyl perindopril and thus that of perindopril. This eventually necessitates extra purifications in the tert. butyl amine salt formation stage, incurring heavy losses of the final product, perindopril erbumine.
From the above description it is clear that the key to the success of the process is the purity of benzyl ester of perindopril obtained after the coupling of intermediate compounds of Formula II & III. The present invention directs to address these problems, where a means for the isolation of benzylperindopril of Formula IV is provided to get rid of the impurities resulting from the peptide coupling reaction and thereby reflecting in high purity of perindopril erbumine, the subject of the present invention.